In general, therapeutic agents for the treatment of various diseases are administered in one of two modalities: systemic or local. Systemic delivery involves the administration of a therapeutic agent at a discrete location remote from the afflicted locale, followed by dispersal of the agent throughout the patient's body including, of course, to the target site or organ. In order to insure that a therapeutically effective amount of the agent reaches the afflicted site, it is usually necessary to administer an initial dose substantially greater than the therapeutically effective amount to account for dilution the agent undergoes as it spreads throughout the body and loss of agent due to reaction with bodily components such as enzymes. Systemic delivery is carried out primarily in two ways: introduction of the therapeutic agent into the digestive tract (enteral administration) or into the vascular system (parenteral administration), either directly such as injection into a vein or an artery or indirectly such as injection into a muscle or into the bone marrow. Delivery by each of these routes is strongly influenced by the so-called ADMET factors: absorption, distribution, metabolism, excretion and toxicity. For enteric administration, such factors as a compound's solubility, its stability in the acidic environs of the stomach and its ability to permeate the intestinal wall all affect the extent to which the drug is absorbed and therefore its bioavailability. For parenteral delivery factors such as enzymatic degradation, the lipophilic/hydrophilic partitioning coefficient, protein binding, etc. will affect the bioavailability of an agent.
Local delivery comprises administration of the therapeutic agent at least proximally but preferably directly to the afflicted locale. The ADMET factors tend to be less important than with systemic administration since the agent is being delivered essentially directly to the treatment site. Thus, the initial dose can be at or very close to the therapeutically effective amount. With time, some of the locally delivered therapeutic agent may diffuse over a wider region but such is not the intent of localized delivery and the concentration of the diffused agent will ordinarily be sub-therapeutic, i.e., too low to have a beneficial effect.
While diffusion of a therapeutic agent affects both systemic and local delivery modalities, it is particularly troublesome with regard to localized delivery where the amount of therapeutic agent being delivered is often as close to the minimum effective concentration as possible to avoid secondary problems such as toxicity and other undesirable side effects. With regard to vascular disorders, the therapeutic agent must usually traverse the endothelium, a layer of cells that line the interior surface of all blood vessels, and all or a portion of the media if the agent is administered within the lumen of the vessel. If the agent is administered exterior to the vessel then it must traverse the periadventitia, adventitia, or a portion of the media to reach the targeted site. The rate at which the therapeutic agent penetrates into and ultimately traverses these tissue layers versus the rate at which the therapeutic agent is diffused away from the locale of interest determines how much of the agent must be administered in the first place.
What is needed with regard to the local treatment of vascular disorders is a method of increasing the rate of therapeutic agent traverse of the periadventitia/aventitia/media/endothelium so that less of the agent is lost during the treatment, thereby requiring less agent initially with a concomitant reduction in potential side effects and possibly cost. The current invention provides such a method.